Excess O2 has been found to be deleterious as it can induce oxidant injury to cells in every organ, especially lungs, retina, heart and brain. The importance of oxidant stress has not been limited to mammalian tissues, as other model systems have also been found to respond in a similar fashion. For example, Drosophila melanogaster has similar pathways, and studies on flies have indeed enhanced our fundamental understanding of oxidant stress. In the past decade we have been able to initiate a number of exciting experiments in this model system in order to investigate O2 sensitivity or tolerance. Recently, using an experimental laboratory selection over many generations, we have successfully developed a strain of Drosophila melanogaster that is extraordinarily resistant to high levels of O2 (90%) without any sign of injury! We therefore focus this proposal on the fundamental understanding of hyperoxia susceptibility and tolerance. Our two specific aims are: 1) Determine whether specific candidate genes are important for hyperoxia tolerance in Drosophila using insertional mutagenesis and overexpression techniques. 2) Study the functional role and mechanisms of specific genes in our hyperoxia-selected Drosophila phenotype. The approaches used will include genetic, molecular biological and physiologic techniques. Our long term objectives are to 1) understand the basis for tolerance to hyperoxia in mammals, and 2) take these ideas into the clinic and bedside. In this proposal, scientists and clinicians join efforts to investigate an important clinical problem and understand its basis with the hope to develop better ideas for treatment modalities for conditions such as neurodegenerative diseases, chronic inflammatory diseases, ischemic and reperfusion states in heart and brain and for better therapies in intensive care settings. PUBLIC HEALTH RELEVANCE: In this proposal, we are studying the reasons why flies that have been selected experimentally over many generations resist very high O2 levels. Since the majority of disease genes in humans are present in flies, studying flies and the mechanisms that operate in these organisms becomes important and useful. Indeed, in the past we have been able to use fly genes to make human cells more resistant to certain stresses.